Olaparib

Olaparib (AZD2281;KU0059436) is a potent and oral PARP inhibitor with IC50s of 5 and 1 nM for PARP1 and PARP2, respectively.
Olaparib is a member of the class of N-acylpiperazines obtained by formal condensation of the carboxy group of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid with the free amino group of N-(cyclpropylcarbonyl)piperazine; used to treat advanced ovarian cancer. It has a role as an antineoplastic agent, an EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor and an apoptosis inducer. It is a N-acylpiperazine, a member of cyclopropanes, a member of monofluorobenzenes and a member of phthalazines.|Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death. Olaparib is available as oral tablets marketed under the brand name Lynparza and was initially indicated as a maintenance therapy or monotherapy for the treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. On January 12, 2018, FDA expanded the approved use of Lynparza to include chemotherapy-experienced patients with germline breast cancer susceptibility gene (BRCA) mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. In a randomized clinical trial involving patients with HER2-negative metastatic breast cancer with a germline BRCA mutation, the median progression-free survival for patients taking Lynparza was 7 months compared to 4.2 months for patients taking chemotherapy only. Patient selection for this newly-approved indication can be performed based on an FDA-approved genetic test, called the BRACAnalysis CDx. Moreover, in December of 2018 the FDA further approved the categorization and use of Lynparza (olaparib) as frontline maintenance therapy in ovarian cancer, making the medication the first time a PARP inhibitor has been approved in the first-line maintenance setting. This new approval for frontline maintenance now allows patients who have had surgery and complete or partial response to platinum-based therapy after being first diagnosed with the cancer to be treated with olaparib to decrease the risk of recurrence or delay it significantly. This approval is based on findings from the phase 3 SOLO-1 trial for olaparib, which demonstrated the capacity for the agent to reduce the risk of disease progression or death by 70% in patients with BRCA-mutant advanced ovarian cancer who were in complete or partial response to platinum-based chemotherapy. It is expected that the ability to offer this important first-line maintenance treatment option to eligible patients may slow down or even stop the natural course of disease progression.|Olaparib is a Poly(ADP-Ribose) Polymerase Inhibitor. The mechanism of action of olaparib is as a Poly(ADP-Ribose) Polymerase Inhibitor.|Olaparib is a small molecule inhibitor of poly ADP-ribose polymerase and is used as an antineoplastic agent in the therapy of refractory and advanced ovarian carcinoma. Olaparib therapy is associated with a low rate of transient elevations in serum aminotransferase during therapy and has not been linked to instances of clinically apparent liver injury.|Olaparib is a small molecule inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Olaparib selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single strand DNA breaks; PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins and can be activated by single-stranded DNA breaks.